The role of timing in frozen embryo transfer
2022; Elsevier BV; Volume: 118; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2022.08.009
ISSN1556-5653
AutoresSarah Lensen, Daniel Lantsberg, David K. Gardner, Azzahra Daniveruszhka Sophian, Namira Wandafiana, Mohan S. Kamath,
Tópico(s)Ovarian function and disorders
ResumoThe process of implantation is characterized by a complex cross-talk between the endometrium and the blastocyst, with the endometrium only being receptive to implantation during a transient window of implantation of approximately 2–3 days during the midsecretory phase. The timing of embryo transfer, including frozen embryo transfer, is therefore critical to the success of implantation. In this article, we discuss various elements that may guide the timing of frozen embryo transfer, including the role of endometrial characteristics such as thickness, days postovulation or length of progesterone administration, stage of the embryo, and the application of endometrial receptivity tests to guide personalized embryo transfer. The process of implantation is characterized by a complex cross-talk between the endometrium and the blastocyst, with the endometrium only being receptive to implantation during a transient window of implantation of approximately 2–3 days during the midsecretory phase. The timing of embryo transfer, including frozen embryo transfer, is therefore critical to the success of implantation. In this article, we discuss various elements that may guide the timing of frozen embryo transfer, including the role of endometrial characteristics such as thickness, days postovulation or length of progesterone administration, stage of the embryo, and the application of endometrial receptivity tests to guide personalized embryo transfer. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/35577 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/35577 Embryo developmental stage and quality as well as endometrial receptivity are key determinants of a successful implantation and healthy pregnancy (1Gardner D.K. Lane M. Stevens J. Schlenker T. Schoolcraft W.B. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer.Fertil Steril. 2000; 73: 1155-1158Abstract Full Text Full Text PDF PubMed Scopus (1369) Google Scholar, 2Salamonsen L.A. Evans J. Nguyen H.P. Edgell T.A. The microenvironment of human implantation: determinant of reproductive success.Am J Reprod Immunol. 2016; 75: 218-225Crossref PubMed Scopus (126) Google Scholar). Implantation requires sequential apposition, attachment, and invasion of the blastocyst into the endometrial epithelium to establish a pregnancy. This union is characterized by a complex cross-talk between the endometrium and the blastocyst, with the endometrium only being receptive to implantation during a transient window of implantation of approximately 2–3 days during the midsecretory phase (3Navot D. Scott R.T. Droesch K. Veeck L.L. Liu H.C. Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro.Fertil Steril. 1991; 55: 114-118Abstract Full Text PDF PubMed Scopus (257) Google Scholar). Although the quality of the blastocyst has generally been viewed as of greatest importance to the likelihood of conception, the role of the endometrium has come under increasing focus, with recent emphasis placed on the determination of exactly when and how to diagnose a receptive endometrium. As technology has advanced, the determination of the window of implantation has progressed from histology of endometrial tissue, including assessment of endometrial thickness and pattern, to the application of gene expression and associated omics. The timing of frozen embryo transfer (FET) relies on our understanding of this window of implantation, ensuring embryos are placed into the uterus at a time in which the endometrium is optimized to facilitate implantation. This article discusses considerations for the timing of FET, specifically focused on the role of endometrial thickness; timing of transfer relative to ovulation or length of progesterone administration, stage of the embryo, and the application of endometrial receptivity tests to guide personalized embryo transfer. Although many studies have implicated endometrial thickness, blood flow, and pattern as the prognostic determinants of a successful embryo transfer, there is still no consensus on the importance of endometrial ultrasound characteristics for decision-making related to the embryo transfer. A meta-analysis from 2014, which included 22 studies and over 10,000 cycles, concluded that women with thin endometrium (≤ 7 mm) were observed to experience low pregnancy rates; however, the use of endometrial thickness in general had a limited capacity to predict the probability of conception from in vitro fertilization (IVF) (4Kasius A. Smit J.G. Torrance H.L. Eijkemans M.J. Mol B.W. Opmeer B.C. et al.Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis.Hum Reprod Update. 2014; 20: 530-541Crossref PubMed Scopus (393) Google Scholar). An additional meta-analysis, again in the general IVF population, also demonstrated that low endometrial thickness was associated with poor IVF outcomes (5Gao G. Cui X. Li S. Ding P. Zhang S. Zhang Y. Endometrial thickness and IVF cycle outcomes: a meta-analysis.Reprod Biomed Online. 2020; 40: 124-133Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). The applicability of endometrial thickness for FET remains unclear as these meta-analyses mostly included studies among women undergoing fresh embryo transfer. A correlation between endometrial thickness and reproductive outcomes has also been demonstrated in FET studies; however, results have been conflicting (6Bu Z. Wang K. Dai W. Sun Y. Endometrial thickness significantly affects clinical pregnancy and live birth rates in frozen-thawed embryo transfer cycles.Gynecol Endocrinol. 2016; 32: 524-528Crossref PubMed Scopus (62) Google Scholar, 7El-Toukhy T. Coomarasamy A. Khairy M. Sunkara K. Seed P. Khalaf Y. et al.The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles.Fertil Steril. 2008; 89: 832-839Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 8Mahutte N. Hartman M. Meng L. Lanes A. Luo Z.C. Liu K.E. Optimal endometrial thickness in fresh and frozen-thaw in vitro fertilization cycles: an analysis of live birth rates from 96,000 autologous embryo transfers.Fertil Steril. 2022; 117: 792-800Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 9Dain L. Bider D. Levron J. Zinchenko V. Westler S. Dirnfeld M. Thin endometrium in donor oocyte recipients: enigma or obstacle for implantation?.Fertil Steril. 2013; 100: 1289-1295Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 10Shakerian B. Turkgeldi E. Yildiz S. Keles I. Ata B. Endometrial thickness is not predictive for live birth after embryo transfer, even without a cutoff.Fertil Steril. 2021; 116: 130-137Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). In the largest retrospective cohort, including a total of 20,114 FET cycles, endometrial thickness was shown to significantly affect clinical pregnancy and live birth rates, which were observed to decrease with each millimeter <7 mm (11Liu K.E. Hartman M. Hartman A. Luo Z.C. Mahutte N. The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers.Hum Reprod. 2018; 33: 1883-1888Crossref PubMed Scopus (188) Google Scholar). Live birth rates were 28.4%, 27.4%, 23.7%, 15%, and 21.2% for endometrial thicknesses measuring 8, 7–7.9, 6–6.9, 5–5.9, and 4–4.9 mm, respectively. It is worth noting that reasonable outcomes were obtained with even the lowest endometrial thickness; live birth rates remained fair (15%–21%) among patients with an endometrial thickness measuring 4–6 mm in FET cycles. Although some evidence suggests endometrial thickness is a useful tool in deciding on cycle cancellation, freezing of all embryos, or refraining from further IVF treatment (4Kasius A. Smit J.G. Torrance H.L. Eijkemans M.J. Mol B.W. Opmeer B.C. et al.Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis.Hum Reprod Update. 2014; 20: 530-541Crossref PubMed Scopus (393) Google Scholar, 3Navot D. Scott R.T. Droesch K. Veeck L.L. Liu H.C. Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro.Fertil Steril. 1991; 55: 114-118Abstract Full Text PDF PubMed Scopus (257) Google Scholar, 12Stentz N. Devine K. Through thick and thin: time to stop worrying about endometrial thickness?.Fertil Steril. 2021; 116: 71-72Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar), results from other studies are conflicting, and the evidence remains limited by the retrospective nature of these studies, small sample sizes, and an associated lack of power (6Bu Z. Wang K. Dai W. Sun Y. Endometrial thickness significantly affects clinical pregnancy and live birth rates in frozen-thawed embryo transfer cycles.Gynecol Endocrinol. 2016; 32: 524-528Crossref PubMed Scopus (62) Google Scholar, 7El-Toukhy T. Coomarasamy A. Khairy M. Sunkara K. Seed P. Khalaf Y. et al.The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles.Fertil Steril. 2008; 89: 832-839Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 11Liu K.E. Hartman M. Hartman A. Luo Z.C. Mahutte N. The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers.Hum Reprod. 2018; 33: 1883-1888Crossref PubMed Scopus (188) Google Scholar, 13Basir G.S. O W.S. So W.W. Ng E.H. Ho P.C. Evaluation of cycle-to-cycle variation of endometrial responsiveness using transvaginal sonography in women undergoing assisted reproduction.Ultrasound Obstet Gynecol. 2002; 19: 484-489Crossref PubMed Scopus (72) Google Scholar). One reason for the conflicting findings could be because of intraobserver variations (14Epstein E. Valentin L. Intraobserver and interobserver reproducibility of ultrasound measurements of endometrial thickness in postmenopausal women.Ultrasound Obstet Gynecol. 2002; 20: 486-491Crossref PubMed Scopus (42) Google Scholar), which may be of greater significance in retrospective studies. Another possible explanation for the conflicting results is the variability in cut-off for defining thin endometrium (7El-Toukhy T. Coomarasamy A. Khairy M. Sunkara K. Seed P. Khalaf Y. et al.The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles.Fertil Steril. 2008; 89: 832-839Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 15Gonen Y. Casper R.F. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF).J In Vitro Fert Embryo Transf. 1990; 7: 146-152Crossref PubMed Scopus (314) Google Scholar, 16Coulam C.B. Bustillo M. Soenksen D.M. Britten S. Ultrasonographic predictors of implantation after assisted reproduction.Fertil Steril. 1994; 62: 1004-1010Abstract Full Text PDF PubMed Scopus (215) Google Scholar, 17Shapiro H. Cowell C. Casper R.F. The use of vaginal ultrasound for monitoring endometrial preparation in a donor oocyte program.Fertil Steril. 1993; 59: 1055-1058Abstract Full Text PDF PubMed Google Scholar). Although endometrial thickness of <7mm is commonly associated with reduced pregnancy rates and used as a cut-off in many research studies and clinical decisions (4Kasius A. Smit J.G. Torrance H.L. Eijkemans M.J. Mol B.W. Opmeer B.C. et al.Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis.Hum Reprod Update. 2014; 20: 530-541Crossref PubMed Scopus (393) Google Scholar), a recent large retrospective study of more than 10,000 cycles suggested that the cut-off point should be 8.7 mm. These investigators reported that clinical pregnancy and live birth rates increase with every millimeter increment of endometrial thickness up to 8.7 mm, at which point they appear to plateau (18Shaodi Z. Qiuyuan L. Yisha Y. Cuilian Z. The effect of endometrial thickness on pregnancy outcomes of frozen-thawed embryo transfer cycles which underwent hormone replacement therapy.PLoS One. 2020; 15e0239120Crossref PubMed Scopus (21) Google Scholar). According to a large recent study of 96,000 cycles, importance of endometrial thickness may differ between fresh and FET cycles (8Mahutte N. Hartman M. Meng L. Lanes A. Luo Z.C. Liu K.E. Optimal endometrial thickness in fresh and frozen-thaw in vitro fertilization cycles: an analysis of live birth rates from 96,000 autologous embryo transfers.Fertil Steril. 2022; 117: 792-800Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). In fresh cycles, live birth rates were shown to increase with increasing thickness of up to 10–12 mm, whereas in FET cycles live birth rates appear to plateau after 7–10 mm. It is possible that the difference in endometrial thickness thresholds between fresh and FET cycles reflects the impact of premature endometrial luteinization, early progesterone rise resulting in epigenetic modification of endometrium, or a premature appearance of the implantation window in a proportion of fresh cycles (19Xiong Y. Wang J. Liu L. Chen X. Xu H. Li T.C. et al.Effects of high progesterone level on the day of human chorionic gonadotrophin administration in in vitro fertilization cycles on epigenetic modification of endometrium in the peri-implantation period.Fertil Steril. 2017; 108: 269-276.e1Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 20Labarta E. Martínez-Conejero J.A. Alamá P. Horcajadas J.A. Pellicer A. Simón C. et al.Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis.Hum Reprod. 2011; 26: 1813-1825Crossref PubMed Scopus (275) Google Scholar, 21Bosch E. Valencia I. Escudero E. Crespo J. Simón C. Remohí J. et al.Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome.Fertil Steril. 2003; 80: 1444-1449Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 22Kolb B.A. Paulson R.J. The luteal phase of cycles utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation.Am J Obstet Gynecol. 1997; 176: 1262-1269Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 23Huang C.C. Lien Y.R. Chen H.F. Chen M.J. Shieh C.J. Yao Y.L. et al.The duration of pre-ovulatory serum progesterone elevation before hCG administration affects the outcome of IVF/ICSI cycles.Hum Reprod. 2012; 27: 2036-2045Crossref PubMed Scopus (71) Google Scholar). However, studies are also conflicting on this point. In a study of 768 hormone replacement therapy (HRT) FET cycles, an endometrial thickness of 9–14 mm was associated with higher pregnancy rates compared with an endometrial thickness of 7–8 mm (7El-Toukhy T. Coomarasamy A. Khairy M. Sunkara K. Seed P. Khalaf Y. et al.The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles.Fertil Steril. 2008; 89: 832-839Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), and in another study of 2,997 FETs, endometrial thickness <9 mm was associated with lower live birth rates compared with those ≥9 mm, but no significant difference was observed between outcomes at 9–13 mm compared with those at ≥14 mm (6Bu Z. Wang K. Dai W. Sun Y. Endometrial thickness significantly affects clinical pregnancy and live birth rates in frozen-thawed embryo transfer cycles.Gynecol Endocrinol. 2016; 32: 524-528Crossref PubMed Scopus (62) Google Scholar). Decreased endometrial thickness may also have significance beyond reproductive outcomes. Thin endometrium has been shown to be independently associated with increased risk of obstetric and neonatal complications in sub fertile women with polycystic ovary syndrome having singleton live births after FET (24Mouhayar Y. Franasiak J.M. Sharara F.I. Obstetrical complications of thin endometrium in assisted reproductive technologies: a systematic review.J Assist Reprod Genet. 2019; 36: 607-611Crossref PubMed Scopus (37) Google Scholar, 25Hu K.L. Kawai A. Hunt S. Li W. Li X. Zhang R. et al.Endometrial thickness in the prediction of neonatal adverse outcomes in frozen cycles for singleton pregnancies.Reprod Biomed Online. 2021; 43: 553-560Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 26He L. Zhang Z. Li H. Li Y. Long L. He W. Correlation between endometrial thickness and perinatal outcome for pregnancies achieved through assisted reproduction technology.J Perinat Med. 2019; 48: 16-20Crossref PubMed Scopus (11) Google Scholar, 27Huang J. Lin J. Xia L. Tian L. Xu D. Liu P. et al.Decreased endometrial thickness is associated with higher risk of neonatal complications in women with polycystic ovary syndrome.Front in Endocrinol. 2021; 12766601Crossref Scopus (6) Google Scholar). For each millimeter decrease in endometrial thickness, they observed a 9%, 14%, and 22% high risk of preterm birth, low birth weight, and small for gestational age, respectively (27Huang J. Lin J. Xia L. Tian L. Xu D. Liu P. et al.Decreased endometrial thickness is associated with higher risk of neonatal complications in women with polycystic ovary syndrome.Front in Endocrinol. 2021; 12766601Crossref Scopus (6) Google Scholar). Other features of the endometrium are also suggested to be predictive of the probability of implantation. Endometrial compaction, as defined by a decrease in endometrial thickness at the time of warmed blastocyst transfer, occurs in approximately 69% of FET cycles (28Haas J. Smith R. Zilberberg E. Nayot D. Meriano J. Barzilay E. et al.Endometrial compaction (decreased thickness) in response to progesterone results in optimal pregnancy outcome in frozen-thawed embryo transfers.Fertil Steril. 2019; 112: 503-509.e1Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). The presence of endometrial compaction was reported to be a favorable factor for pregnancy rates, when compared with cycles with no change or an increase in endometrial thickness on the day of transfer (28Haas J. Smith R. Zilberberg E. Nayot D. Meriano J. Barzilay E. et al.Endometrial compaction (decreased thickness) in response to progesterone results in optimal pregnancy outcome in frozen-thawed embryo transfers.Fertil Steril. 2019; 112: 503-509.e1Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 29Zilberberg E. Smith R. Nayot D. Haas J. Meriano J. Barzilay E. et al.Endometrial compaction before frozen euploid embryo transfer improves ongoing pregnancy rates.Fertil Steril. 2020; 113: 990-995Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). However, several recent large-scale studies have refuted this suggestion (30Bu Z. Yang X. Song L. Kang B. Sun Y. The impact of endometrial thickness change after progesterone administration on pregnancy outcome in patients transferred with single frozen-thawed blastocyst.Reprod Biol Endocrinol. 2019; 17: 99Crossref PubMed Scopus (49) Google Scholar, 31Ye J. Zhang J. Gao H. Zhu Y. Wang Y. Cai R. et al.Effect of endometrial thickness change in response to progesterone administration on pregnancy outcomes in frozen-thawed embryo transfer: analysis of 4465 cycles.Front Endocrinol (Lausanne). 2020; 11546232Crossref Scopus (17) Google Scholar, 32Huang J. Lin J. Cai R. Lu X. Song N. Gao H. et al.Significance of endometrial thickness change after human chorionic gonadotrophin triggering in modified natural cycles for frozen-thawed embryo transfer.Ann Transl Med. 2020; 8: 1590Crossref PubMed Google Scholar, 33Riestenberg C. Quinn M. Akopians A. Danzer H. Surrey M. Ghadir S. et al.Endometrial compaction does not predict live birth rate in single euploid frozen embryo transfer cycles.J Assist Reprod Genet. 2021; 38: 407-412Crossref PubMed Scopus (23) Google Scholar). Endometrial blood flow in fresh IVF cycles, either on the day of trigger of embryo transfer, has been shown to correlate with pregnancy rates and could potentially help identify the appropriate timing for FET (34Wang J. Xia F. Zhou Y. Wei X. Zhuang Y. Huang Y. Association between endometrial/subendometrial vasculature and embryo transfer outcome: a meta-analysis and subgroup analysis.J Ultrasound Med. 2018; 37: 149-163Crossref PubMed Scopus (27) Google Scholar), and indeed the predictive value of sub endometrial vasculature flow has also been shown to have some value in predicting pregnancy in FET cycles (35Ng E.H. Chan C.C. Tang O.S. Yeung W.S. Ho P.C. The role of endometrial and subendometrial vascularity measured by three-dimensional power Doppler ultrasound in the prediction of pregnancy during frozen-thawed embryo transfer cycles.Hum Reprod. 2006; 21: 1612-1617Crossref PubMed Scopus (64) Google Scholar, 36Mishra V.V. Agarwal R. Sharma U. Aggarwal R. Choudhary S. Bandwal P. Endometrial and subendometrial vascularity by three-dimensional (3D) power Doppler and its correlation with pregnancy outcome in frozen embryo transfer (FET) cycles.J Obstet Gynaecol India. 2016; 66: 521-527Crossref PubMed Scopus (16) Google Scholar, 37Sadek S. Matitashvili T. Kovac A. Ramadan H. Stadtmauer L. Assessment of uterine receptivity by endometrial and sub-endometrial blood flow using SlowflowHD in hormone prepared frozen embryo transfer cycles: a pilot study.J Assist Reprod Genet. 2022; 39: 1069-1079Crossref PubMed Scopus (6) Google Scholar). However, results are conflicting, and the accuracy of these indices in predicting FET outcomes must be further evaluated in large-scale studies (38Nandi A. Martins W.P. Jayaprakasan K. Clewes J.S. Campbell B.K. Raine-Fenning N.J. Assessment of endometrial and subendometrial blood flow in women undergoing frozen embryo transfer cycles.Reprod Biomed Online. 2014; 28: 343-351Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Progesterone plays an important role in the development of the endometrial window of implantation (39Mackens S. Santos-Ribeiro S. van de Vijver A. Racca A. Van Landuyt L. Tournaye H. et al.Frozen embryo transfer: a review on the optimal endometrial preparation and timing.Hum Reprod. 2017; 32: 2234-2242Crossref PubMed Scopus (200) Google Scholar, 40Mumusoglu S. Polat M. Ozbek I.Y. Bozdag G. Papanikolaou E.G. Esteves S.C. et al.Preparation of the endometrium for frozen embryo transfer: a systematic review.Front Endocrinol (Lausanne). 2021; 12: 688237Crossref PubMed Scopus (49) Google Scholar). In HRT cycles, once optimal endometrial thickness is achieved by exogenous estrogen, progesterone is administered to initiate secretory changes in the endometrium. The length of progesterone exposure before embryo transfer is important for the development of a receptive endometrium. The optimal length of progesterone exposure before FET in artificial cycles is unclear because of the paucity of data. We identified 3 randomized-controlled trials (RCTs) and 2 retrospective studies which evaluated the varying duration of progesterone therapy before FET in HRT cycles. The impact of 5th vs. 3rd day of progesterone administration before FET was studied in an open label RCT among women undergoing vitrified-warmed cleavage stage embryo transfer (41van de Vijver A. Polyzos N.P. Van Landuyt L. Mackens S. Stoop D. Camus M. et al.What is the optimal duration of progesterone administration before transferring a vitrified-warmed cleavage stage embryo? A randomized controlled trial.Hum Reprod. 2016; 31: 1097-1104Crossref PubMed Scopus (49) Google Scholar). The day 3 embryos were cultured overnight and transferred as day 4 embryos. The live birth rate per initiated cycle did not differ significantly between the 2 groups (20% vs. 16%; odds ratio [OR], 1.3; 95% confidence interval [CI], 0.73–2.73). However, early pregnancy loss was significantly higher in the day 3 group (36.2% vs. 55.2%; OR, 0.46; 95% CI, 0.22–0.97), and the investigators concluded that the short duration of progesterone therapy may negatively impact the FET outcomes. In another open label RCT, the same investigators evaluated 7th vs. 5th day of progesterone supplementation in vitrified-warmed blastocyst transfer cycles (n = 303) (42van de Vijver A. Drakopoulos P. Polyzos N.P. Van Landuyt L. Mackens S. Santos-Ribeiro S. et al.Vitrified-warmed blastocyst transfer on the 5th or 7th day of progesterone supplementation in an artificial cycle: a randomised controlled trial.Gynecol Endocrinol. 2017; 33: 783-786Crossref PubMed Scopus (25) Google Scholar). There was no significant difference in the live birth rate per initiated cycle (25.7% vs. 31.1%; OR, 0.76; 95% CI, 0.46–1.26). The early pregnancy loss rate was also similar in both the groups (40% vs. 40.82%; OR, 0.99; 95% CI, 0.52–1.90). The investigators concluded that the reduced length of progesterone therapy did not affect the clinical pregnancy rates in FET cycles. However, because the trial was powered to detect a difference of 16 percentage points, a smaller benefit could not be excluded. One further RCT evaluated effectiveness of 7th vs. 6th day of progesterone administration before frozen-thawed blastocyst transfer (n = 49) (43Glujovsky D. Pesce R. Fiszbajn G. Sueldo C. Hart R.J. Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.Cochrane Database Syst Rev. 2010; 1: CD006359PubMed Google Scholar, 44Ding J. Rana N. Dmowski W.P. Length of progesterone treatment before transfer and implantation rates of frozen-thawed blastocysts.Fertil Steril. 2007; 88: S330-S331Abstract Full Text Full Text PDF Google Scholar). The clinical pregnancy rate did not differ significantly between the 2 groups; however, the quality of evidence was graded as very low (OR, 0.75; 95% CI, 0.24–2.34). In a cohort study, the outcome of vitrified-warmed blastocyst transfer was compared when embryo transfer was performed on 7th (n = 346) vs. 6th (n = 273) day of progesterone administration (45Roelens C. Santos-Ribeiro S. Becu L. Mackens S. Van Landuyt L. Racca A. et al.Frozen-warmed blastocyst transfer after 6 or 7 days of progesterone administration: impact on live birth rate in hormone replacement therapy cycles.Fertil Steril. 2020; 114: 125-132Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). The live birth rate was similar between both the groups (36.6% vs. 36.6%; adjusted OR, 1.07; 95% CI, 0.74–1.55). In another cohort study, FET performed on the 7th vs. 6th day of progesterone initiation was compared among women undergoing single vitrified-warmed blastocyst transfer (46Yang X. Bu Z. Hu L. Live birth rate of frozen-thawed single blastocyst transfer after 6 or 7 days of progesterone administration in hormone replacement therapy cycles: a propensity score-matched cohort study.Front Endocrinol (Lausanne). 2021; 12: 706427Crossref PubMed Scopus (5) Google Scholar). After case matching using propensity scores, a total of 1,400 women were included. The live birth rate was significantly low for the 7th day group compared with the 6th day group (31.57% vs. 38.43%; P=.01). There is absence of data on whether timing of progesterone initiation in HRT cycle needs any alteration on the basis of different routes of progesterone administration. To summarize the current evidence, the length of progesterone equivalent to the embryonic age + 1 day (6th day and 4th day of progesterone administration for the blastocyst and cleavage stage embryo transfer, respectively) appears to optimize the reproductive outcome following FET in HRT cycle (39Mackens S. Santos-Ribeiro S. van de Vijver A. Racca A. Van Landuyt L. Tournaye H. et al.Frozen embryo transfer: a review on the optimal endometrial preparation and timing.Hum Reprod. 2017; 32: 2234-2242Crossref PubMed Scopus (200) Google Scholar). A progesterone therapy duration shorter than the embryonic age may lead to increased pregnancy loss. However, owing to conflicting study results, it is unclear whether the progesterone administration equivalent to embryonic age + 2 days leads to poor outcomes compared with progesterone duration of embryonic age + 1 day. There is growing evidence of benefit with the use of natural and modified natural cycles over HRT cycles during FET treatment (40Mumusoglu S. Polat M. Ozbek I.Y. Bozdag G. Papanikolaou E.G. Esteves S.C. et al.Preparation of the endometrium for frozen embryo transfer: a systematic review.Front Endocrinol (Lausanne). 2021; 12: 688237Crossref PubMed Scopus (49) Google Scholar). In a natural cycle FET, the ovulation occurs spontaneously whereas in the modified natural cycle protocol, ovulation is triggered by human chorionic gonadotropin (hCG) administration (39Mackens S. Santos-Ribeiro S. van de Vijver A. Racca A. Van Landuyt L. Tournaye H. et al.Frozen embryo transfer: a review on the optimal endometrial preparation and timing.Hum Reprod. 2017; 32: 2234-2242Crossref PubMed Scopus (200) Google Scholar). There is very limited data on optimal timing of FET in natural or modified natural cycle protocols. We identified one RCT evaluating the effectiveness of administering hCG trigger vs. spontaneous luteinizing hormone (LH) surge which indirectly explores issues around timing of ET in natural /modified natural cycles. In an RCT, investigators compared spontaneous LH surge vs. hCG induced ovulation during FET of cleavage stage embryos (47Fatemi H.M. Kyrou D. Bourgain C. Van den Abbeel E. Griesinger G. Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle.Fertil Steril. 2010; 94: 2054-2058Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The FET was performed 5 days after recording spontaneous LH surge in the study group. Similarly, the embryo tra
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